Factors Influencing the Allergenicity and Adjuvanticity of Allergens

Stephan Deifl; Barbara Bohle

Disclosures

Immunotherapy. 2011;3(7):881-893. 

In This Article

Dimerization/Oligomerization

Apart from the induction of IgE antibodies, an important feature of allergens is their capacity to cross-link specific IgEs bound to high-affinity receptors on the surface of effector cells resulting in the clinical manifestations of IgE-mediated hypersensitivity. In principle, at least two epitopes must be contained in an allergen to cross-link two IgE molecules. However, on the surface of small allergens, this requirement may not always be fulfilled. Another possibility may be the appearance of allergens as dimers/oligomers to induce effector cell activation. Indeed, detailed investigations of 3D structures of allergens revealed that several allergens naturally form dimers or oligomers. The major allergen from cow's milk Bos d 5 represents a well-studied example of a transient dimer. Its dissociation constant (Kd = 5 µM) is so high that depending on its concentration Bos d 5 exists as a mixture of monomers and dimers in solution.[76] The monomeric form of Bos d 5 showed less capacity to induce histamine release from basophils.[77] Similarly, monomeric mutants of the cockroach allergen Bla g 2 induced less mediator release from mast cells than the authentic dimeric Bla g 2.[78] Natural dimerization was also demonstrated for the major horse allergen Equ c 1 and allergens in grass pollen from Phleum pratense and Dactylis glomerata, namely Phl p 7 and the group 5 allergens.[79–82] Oligomerization was reported for polcalcins,[83] which represent highly cross-reactive ubiquitous calcium-binding pollen allergens.[84] A recent analysis of 55 crystal structures of allergens showed that 80% of them existed in symmetric dimers or oligomers in the crystals and the formation of transient dimers in solution was confirmed at higher protein concentrations by native mass spectrometry.[77] Definitely, the natural occurrence of allergen dimers/oligomers provides a straightforward explanation of how these proteins can accomplish effective cross-linking of IgE and subsequent activation of effector cells. However, the importance of dimerization/oligomerization for the induction of IgE responses still remains an open issue. In this regard, conflicting results for the Bet v 1 family were obtained. One study demonstrated that dimerization is important for the allergenic reactivity of the major birch pollen allergen in mice[85] because the monomer was less capable of activating memory B cells for IgE production in vivo. A recent study compared the in vivo responses to the monomeric isoform Bet v 1a and Bet v 1d, an isoform with a high tendency to form disulfide-linked aggregates.[86] Bet v 1d activated murine DCs more efficiently than Bet v 1a, which was followed by the production of increased amounts of Th1- as well as Th2-type cytokines. Whereas both isoforms induced similar specific IgE levels, only Bet v 1d induced relevant titers of specific IgG and IgA. This finding suggested that aggregation of allergens induced protective antibody responses. Together, dimers/oligomers of allergens induce stronger immune responses as compared to monomers, possibly due to a 'particle effect' resulting in enhanced internalization by APCs. Whether these altered responses promote the induction of Th2 responses or protective responses needs to be further investigated.

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